Abdominal aortic aneurysm (AAAs) is the most common form of aortic aneurysm and ruptured AAAs cause at least 15,000 deaths each year in the US. Epidemical studies suggest that cigarette smoke increases the risk of AAAs 7.6-fold. However, a causative link between cigarette smoke and AAAs has not been established in human or animals. Our exciting preliminary data indicate that acute infusion of nicotine resulted in significantly increased elastin degradation, enlargement of the aorta, abnormal expression and activation of matrix metalloproteinase 2 (MMP2), and an increased incidence of AAA in ApoE knockout (ApoE-/-) mice. Importantly, we find that genetic deletion of AMP-activated protein kina (AMPK2) markedly reduces the incidence of AAA caused by nicotine or AngII in vivo. Biochemical and biological analysis reveal that phosphorylation of AP-2 by AMPK2 increases its binding to the MMP2 promoter resulting in transcription of pro-MMP2 and conversion into active MMP2. Thus, Thus, we hypothesize that the activation of AMPK2 by nicotine in cigarette smoke instigates AAAs by the induction of MMP2 leading to subsequent damage of the vessel wall matrix. We will first establish if AMPK2 is required for nicotine-instigated destruction of the vessel wall and aneurysm formation in mice in vivo. After that, we will investigate if nicotine via AMPK2 causes aberrant expression of MMP2 and if MMP2 is responsible for nicotine-enhanced damage of the vessel wall matrix in mice in vivo. Finally, we will elucidate molecular mechanisms by which nicotine and cigarette smoke activates AMPK and how AMPK2 activation regulates the expression and activity of MMP2 and their inhibitors, TIMPs, in VSMC and macrophages, two major cell types in the aneurismal vessels. Proposed studies on the link between cigarette smoke, MMPs and aneurysm pathogenesis are highly significant, as the achievement of its goals will directly lead to a better understanding of the fundamental pathologic mechanisms that contribute to the progression of aneurismal degeneration by smoking and other risk factors, and most importantly, could provide specific possibilities for therapeutic approaches. PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAAs) is the most common form of aortic aneurysm and uncontrolled growth of AAAs frequently leads to rupture resulting in approximately 80% mortality. Epidemical studies suggest that cigarette smoke increases the risk of AAAs 7.6-fold and smoking is the only modifiable factor associated with the development, expansion, and rupture of AAAs. In this application, a combination of pharmacological, molecular, and genetic means with gain-of-function and loss-of-function approaches will be used to establish a causative link between cigarette smoke and AAAs in animals in vivo. The completion of this project will increase our understanding of the fundamental pathologic mechanisms that contribute to the progression of aneurismal degeneration by smoking and other risk factors, and most importantly, could provide specific possibilities for therapeutic approaches.